Seasonal and universal Vaccination in aged populations with pre-existing immunity

项目总结 目前基于高变量血凝素(HA)蛋白的流感疫苗未能提供 有效的交叉保护。在老年人群中接种疫苗的效果很低，即使是预先存在的 豁免权。既往免疫对普及性和季节性免疫原性和免疫效力的影响 在老年人群中，疫苗接种在很大程度上仍然没有得到很好的了解。开发新的流感疫苗和 提高幼稚和老年既往宿主交叉保护效力的疫苗接种策略 豁免权是当务之急。在幼稚动物身上测试诱导交叉保护的单一保守抗原靶点 模型包括甲型流感病毒M2胞外区(M2e)、HA茎区和神经氨酸酶(NA)。 已报告，但不足以翻译给人类。幼稚和老年宿主的多靶点通用疫苗 是否具有预先存在的免疫力仍有待开发。 我们开发了M2e(5xM2e)的异源串联重复序列，呈现在免疫原性病毒样上 颗粒物(5xM2e VLP)。接种5xM2e VLP有效地扩大了交叉保护范围，但 不太理想。应进一步改进通用疫苗。我们的初步研究发现 M2e和NA免疫增强交叉保护的协同效应。因此，作为一个新的普遍存在的 候选疫苗，我们研制了包含多亚型NA和5xM2e的多NA+5xM2e VLP疫苗 相同的VLP粒子。此外，我们新设计了基因连锁的新型重组M2e-茎 通用蛋白疫苗有效地诱导M2E和HA-茎免疫，并授予广泛的杂交 群体保护。佐剂全民接种将通过以下方式克服衰老相关的免疫衰老 在原有免疫状态下激活幼稚宿主或老年人群中的T和B免疫细胞。 在这个项目中，我们将检验新的通用疫苗诱导多重免疫(M2e， STREK，NA)将增强交叉保护的广度和有效性，在患有或 没有预先存在的豁免权。根据目标1，我们将在#年确定多目标通用疫苗的效力。 幼年成年小鼠和雪貂在幼稚和先前存在的免疫条件下。在AIM 2研究中，我们将 多靶点新型通用疫苗交叉保护免疫持久性的测定和试验 加强老龄小鼠和雪貂动物模型的交叉保护的疫苗接种策略。在《目标3》中，我们将 青年与老年人多靶向通用疫苗交叉保护免疫机制探讨 老鼠模型。该项目的成果将在翻译科学和 提高流感疫苗交叉保护效果的相关性。

PROJECT SUMMARY Current influenza (flu) vaccination based on hypervariable hemagglutinin (HA) protein fails to provide effective cross protection. The efficacy of vaccination is low in the aged populations even with pre-existing immunity. The impacts of pre-existing immunity on the immunogenicity and efficacy of universal and seasonal vaccination largely remain not well understood in the aged populations. Development of new flu vaccines and vaccination strategies improving cross protective efficacy in young naïve and aged hosts with pre-existing immunity is of high priority. Mono conserved antigenic targets inducing cross protection tested in naïve animal models include the flu A virus M2 extracellular domain (M2e), HA-stalk domains, and neuraminidase (NA) were reported but insufficient for translation to humans. The multi-target universal vaccines in naïve and aged hosts with pre-existing immunity remain to be developed. We developed heterologous tandem repeat of M2e (5xM2e) presented on immunogenic virus-like particles (5xM2e VLP). Vaccination with 5xM2e VLP was effective in broadening cross protection but suboptimal. A further improved universal vaccine should be developed. Our preliminary studies found synergistic effects on improving cross protection by both M2e and NA immunity. Therefore, as a new universal vaccine candidate, we developed a multi NA + 5xM2e VLP vaccine containing multi-subtype NA and 5xM2e on the same VLP particle. In addition, we newly designed genetically linked novel recombinant M2e-stalk universal protein vaccines effectively inducing both M2e and HA-stalk immunity and conferring broad cross- group protection. Adjuvanted universal vaccination will overcome the aging-related immune senescence by activating T and B immune cells in naïve hosts or aged populations under pre-existing immunity. In this project, we will test the hypothesis that new universal vaccination inducing multi immunity (M2e, Stalk, NA) will enhance the breadth and efficacy of cross protection in adult and aged populations with or without pre-existing immunity. Under Aim 1, we will determine the efficacy of multi-target universal vaccines in young adult mice and ferrets under naïve and pre-existing immune conditions. In Aim 2 studies, we will determine the durability of cross protective immunity by multi targeting new universal vaccines and test a vaccination strategy enhancing cross protection in aged mouse and ferret animal models. In the Aim 3, we will investigate cross protective immune mechanisms of multi targeting universal vaccination in young and aged mouse models. The outcomes in this project will be highly significant in the aspect of translational science and relevance to improve the cross protective efficacy of flu vaccination.